Pterygium is a sunlight-related, ocular-surface lesion that can obscure vision. In order to identify specific genes that may play a role in pterygium pathogenesis, we analyzed the global gene expression profile of pterygium in relation to autologous conjunctiva. In addition, we tested whether doxycycline, a matrix metalloproteinase inhibitor, could prevent the migration and growth of human pterygial cells in vitro and in vivo. The microarray data showed both novel and previously-identified extracellular-matrix-related, pro-inflammatory, angiogenic, fibrogenic, and oncogenic genes expressed in human pterygium. There was increased expression of lipocalin 2, which activates matrix metalloproteinases (MMPs). The over-expression of lipocalin 2 is consistent with our previous finding that MMP-9 and other MMPs are highly expressed in pterygium basal epithelial cells. Doxycycline was used to test the hypothesis that MMPs play a role in pterygium migration. This MMP inhibitor reduced the activity of MMP-9 in human pterygial cell cultured medium and substantially decreased pterygial cell migration in the Boyden Chamber Migration Assay. Using the Directed In Vivo Angiogenic Assay, doxycycline decreased pterygial cell-induced blood vessel growth in angioreactors of mice given oral doxycycline by water. A number of genes are associated with pterygium, including angiogenic growth factors and regulators of angiogenesis. Doxycycline, an MMP inhibitor, decreased the level of pterygial cell migration and angiogenesis. Doxycycline is an inexpensive, noninvasive, FDA-approved drug for other ocular diseases that could potentially benefit humans by reducing the vascular growth of pterygia and, therefore, may prove to be vision-saving. The potential for treatment of other diseases exists as well.